As multidrug-resistant bacterial strains emerge in increasing numbers, the need for new kinds of antibiotics is growing. For the last few decades it has been found that a wide range of antimicrobial peptides are secreted by multicellular organisms in response to infection by foreign bacteria, viruses, or fungi (1-4). These form part of the innate immune response to infection, which is short term and fast acting relative to humoral immunity (3). These peptides have been considered as prospective antibiotic agents because their effect is rapid, broad spectrum and indifferent to resistance to standard antibiotics such as penicillin (5-6). Antimicrobial peptides differ dramatically in size, sequence and structure, apparently sharing only amphipathic character and positive charge (1, 5). The proposed mechanisms of action of antimicrobial peptides commonly focus on the interaction between these peptides and the plasma membrane of bacterial cells, even though many antimicrobial peptides also employ more sophisticated mechanisms (7). Recently, the pharmocophore of short cationic antimicrobial peptides has been extensively studied and the results showed that short cationic peptides consisting of only Arginine (R) and Tryptophan (W) could serve as moderately effective antimicrobial agents (8-9).
Besides various advantages over conventional antibiotics, the practical use of antimicrobial peptides, however, are limited by many factors. These peptides are usually more expensive to make, vulnerable to protease degradation, and have relatively high toxicity. A number of nonnatural peptides built from beta-amino acids or peptoids, as well as other peptide mimics have been studied in order to overcome these problems (10-12). In this study, we designed and screened inexpensive small compounds to mimic the hydrophobic-cationic pattern observed in the pharmocophore of small cationic antimicrobial peptides using 1,3,5-triazine as a template. Previous studies showed that possible antimicrobials could be identified through combinatorial libraries constructed to have varieties of tri-substituted 1,3,5-triazines (13).
From the above, it remains that a continuing need exists for the stepwise design and optimization of different functional groups (mainly hydrophobic, bulky or charged groups) on the triazine scaffold in search of potential new antimicrobials, as well as to gain insight as to the structure-function relationship of these agents.
Furthermore, it remains that a continuing need exists for the development of modalities that can deliver effective antibiotic s-triazine compounds in a manner that confers both improved stability and economy of the therapeutic, but importantly, significantly improves the therapeutic efficacy and strength of the resultant molecule. It is toward the fulfillment of these and other related objectives that the present invention is directed.